Phospholipid exchange proteins are soluble proteins capable of catalyzing the translocation of intact phospholipid molecules between phospholipid membranes - both natural and artificial. The apparent mechanism of phospholipid exchange involves interaction of the exchange protein with the membrane surface, after which association is established a phospholipid molecule is abstracted from or inserted into the membrane matrix. It is the nature of this association, between exchange protein and membrane, to which this research program is directed. One experimental approach involves the lipid components of the membrane; hence, variations in phospholipid composition and cholesterol content are investigated. A second approach focuses on the incorporations of membrane proteins into artificial liposome systems and the subsequent effects on phospholipid exchange; these studies, with membranes composed of both lipid and protein, tend toward a more realistic approximation of native membrane structure. The final approach attempts to define what may be a fine-scale control of phospholipid exchange through changes in the physical and chemical properties of the membrane phospholipid bilayer. Thus, in liposomes composed of heterogeneous mixtures of phospholipids, under the influence of temperature, pH, or divalent cations, discrete regions of specific phospholipids may be generated; such regions may be highly fluid (liquid crystalline) or rigidly organized (crystalline) in terms of relative lipid mobility and may interact differently with exchange proteins. These studies into the mechanisms of protein-catalyzed phospholipid exchange will provide insight into the biological roles of these proteins, including, for example, membrane biogenesis. Furthermore, these studies will help establish phospholipid exchange proteins as a discriminating tool in the investigation of protein-lipid interaction in biological membranes.